CN115340561A

CN115340561A - Preparation and application of SHP2 phosphatase fused ring inhibitor

Info

Publication number: CN115340561A
Application number: CN202110529037.3A
Authority: CN
Inventors: 梁永宏; 许志勇; 严文广; 曾兆森; 熊方均
Original assignee: Yaoya Technology Shanghai Co ltd
Current assignee: Yaoya Technology Shanghai Co ltd
Priority date: 2021-05-14
Filing date: 2021-05-14
Publication date: 2022-11-15

Abstract

The invention discloses a preparation method and application of a fused ring inhibitor of SHP2 phosphatase. Particularly, the invention discloses a compound shown in the general formula I, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound as a protein tyrosine phosphatase SHP-2 inhibitor in treating diseases or symptoms such as leukemia, neuroblastoma, melanoma, breast cancer, lung cancer and colon cancer.

Description

Preparation method and application of SHP2 phosphatase fused ring inhibitor

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a novel SHP2 phosphatase inhibitor, and a preparation method and application thereof.

Background

The present invention relates generally to novel compounds, methods for their preparation, and their use as SHP2 phosphatase inhibitors (e.g., for the treatment of cancer).

SHP2 is a non-receptor protein tyrosine phosphatase encoded by PTPN11 gene, and contains two N-terminal Src homology 2 (SH 2) domains, a Protein Tyrosine Phosphatase (PTP) domain and a poorly sequenced C-terminus. X-ray crystallography studies have shown that SHP2 inhibits its own phosphatase activity by blocking access to the catalytic site on the PTP domain using the N-terminal SH2 domain. It has been demonstrated that the binding of a tyrosyl diphosphate protein or peptide (e.g., IRS-1) to the SH2 domain of SHP2 disrupts the N-terminal SH2-PTP domain interaction. This binding allows the substrate to enter the catalytic site and activate the phosphatase.

SHP2 is recruited by RTKs to induce cellular signaling and is involved in multiple intracellular oncogenic signaling cascades, such as the Jak/STAT, PI3K/AKT, RAS/Raf/MAPK, PD-1/PD-L1, and mTOR pathways. Wherein the GTP binding mode, which conducts extracellular signals to the nuclear key gtpase RAS, regulated (dephosphorylation of tyrosine in adaptor/scaffold proteins) by SHP2 to the activated state, exerts carcinogenic effects; on the other hand, SHP2 activation of RAS signals in acquired resistance promotes compensatory activation of signaling pathways (e.g., negative feedback regulation of MEK activates RTK, activating SHP2 and thus downstream pathways), in which case, inhibition of SHP2 may eliminate reactivation of the RAS/Raf/ERK pathway and represent a potential therapeutic strategy as a new strategy to address the problem of RTK resistance.

Moreover, germline or somatic mutations in PTPN11 leading to the overactivation of SHP2 have been identified in a variety of pathophysiological states: developmental disorders Noonan syndrome, hematological malignancies including juvenile myelomonocytic leukemia, myelodysplastic syndrome, B-cell acute lymphocytic leukemia and acute myelogenous leukemia and low frequency solid tumors. Thus, SHP2 is one of the most recently highly attractive targets for developing new therapies for treating various diseases.

Published patent applications on related studies of the SHP2 target have; WO2015107494A1, WO2015107495A1, WO2017211303A1, WO2018057884A1, WO2018136265A1, WO2019167000A1, WO2020033828A1, WO2020063760A1, WO2020081848A1, WO2020247643A1, and the like. Several SHP-2 inhibitors have been in clinical phase, such as TNO-155 developed by Novartis, RMC-4630 developed by Revolition Medicine, and JAB-3068 by Beijing plus Corse. However, there is no SHP-2 inhibitor developed and marketed for the treatment of Noonan's syndrome, leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, gastric cancer, lung cancer and colon cancer. Therefore, the development of SHP-2 inhibitor drugs with good pharmacy is urgently needed.

Disclosure of Invention

A compound having the general formula (I), a stereoisomer, a pharmaceutically acceptable salt, a polymorph, or an isomer thereof, wherein the compound having the general formula (I) has the following structure:

wherein,

each L ₁ Independently at each occurrence is selected from the group consisting of bond, O, CH ₂ NH, CO or S;

each L ₂ Independently at each occurrence selected from the group consisting of a bond, O, CH ₂ 、NH、CONH ₂ CO or S;

each X ₁ 、X ₂ 、X ₃ 、X ₅ 、X ₆ 、X ₇ Independently at each occurrence selected from N, CR ₉ ；

Each R ₉ Independently at each occurrence is selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OC _1-6 、-SC _1-6 、-NHC _1-6 、-N(C _1-6 Alkyl) (C) _1-6 Alkyl), CONH ₂ 、COOH；

Each X ₄ Independently at each occurrence is selected from N, C;

each Ar ₁ Independently at each occurrence, is selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl at each occurrenceIndependently comprise 1,2, 3 or 4 heteroatoms selected from N, O, or S; each Ar ₁ Optionally at each occurrence independently by 1,2, 3, 4, 5 or 6R ₁₉ Substituted or unsubstituted;

each Ar ₂ Independently at each occurrence selected from H, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently at each occurrence comprising 1,2, 3 or 4 heteroatoms selected from N, O, or S; each Ar ₂ Optionally at each occurrence independently by 1,2, 3, 4, 5 or 6R ₁₉ Substituted or unsubstituted;

each R ₁₉ Independently at each occurrence is selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OR ₁₀ 、-C _1-6 Alkylene- (OR) ₁₀ ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SR ₁₀ 、-S-C _1-6 Alkylene- (halogen) _1-3 、-NR ₁₀ R ₁₁ -C1-6 alkylene-NR ₁₀ R ₁₁ 、-C(＝O)R ₁₀ 、-C(＝O)OR ₁₀ 、-OC(＝O)R ₁₀ 、-C(＝O)NR ₁₀ R ₁₁ 、-NR ₁₀ C(＝O)R ₁₁ 、-S(O) ₂ NR ₁₀ R ₁₁ or-C _3-6 A carbocyclic group; each R ₁₉ Independently optionally substituted by 1,2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₁₀ 、-NR ₁₀ R ₁₁ 、-CN、-C(＝O)R ₁₀ 、-C(＝O)OR ₁₀ 、-OC(＝O)R ₁₀ 、-C(＝O)NR ₁₀ R ₁₁ 、-NR ₁₀ C(＝O)R ₁₁ or-S (O) ₂ NR ₆ R ₁₁ Substituted or unsubstituted;

each R ₁₀ And R ₁₁ Independently at each occurrence is selected from hydrogen, deuterium or-C _1-6 Alkyl radical, each R ₁₀ And R ₁₁ Independently and optionally substituted by 1,2. 3, 4, 5 or 6R ₁₉ Substituted or unsubstituted; or R ₁₀ And R ₁₁ Together with the N atom to which they are both attached form a 3-10 membered heterocyclic ring, which 3-10 membered heterocyclic ring may further comprise 1,2, 3 or 4 substituents selected from N, O, S (= O) or S (= O) ₂ And said 3-10 membered heterocyclic ring is independently optionally substituted with 1,2, 3, 4, 5 or 6R ₂₀ Substituted or unsubstituted;

each R ₂₀ Independently at each occurrence, selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OC _1-6 、-C _1-6 Alkylene- (OC) _1-6 ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SC _1-6 、-S-C _1-6 Alkylene- (halogen) _1-3 or-C _3-6 A carbocyclic group;

each X ₈ Independently at each occurrence is selected from CR ₄ R ₅ 、SiR ₄ R ₅ 、NH、O；

Each X ₉ Independently at each occurrence is selected from CR ₆ NH, wherein X ₇ And X ₈ One must be carbon;

each R ₁ Independently at each occurrence is selected from H, deuterium, -C _1-6 An alkyl group;

each R ₂ Independently at each occurrence, selected from H, deuterium, OH, CH ₂ NH ₂ ；

Each R ₃ 、R ₇ 、R ₈ Independently at each occurrence is selected from H, deuterium;

each R ₄ Independently at each occurrence, selected from H, deuterium, OH, C _0-3 NR ₁₂ R ₁₃ ；

Each R ₅ Independently at each occurrence selected from H, deuterium, OH, C _1-6 Alkyl radical, C _1-6 Alkyl substituted by 1,2, 3, 4, 5 or 6 deuterium, OH, methyl, OCH ₃ 5-10 membered heteroaryl;

each R ₆ Independently at each occurrence is selected from H, deuterium, NH ₂ ；

R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ Two of them can be connected in the following way:

R ₁ and R ₂ May adopt CH ₂ NHCH ₂ Are connected to form a thick double ring,

R ₁ and R ₆ Alkylene groups may be used to link to form bridged bicyclic rings,

R ₂ and R ₃ Can adopt NH ₂ Substituted alkylene groups are linked to form a spiro ring,

R ₄ and R ₅ Can be connected to form C _3-12 Cycloalkyl of (C) _3-12 Heterocycloalkyl of (C) _3-12 Bicycloalkyl of, C _3-12 In which C is _3-12 Heterocycloalkyl of (C) _3-12 Independently at each occurrence, contains 1,2, 3, or 4 heteroatoms selected from N, O, or S, each C _3-12 Cycloalkyl of, C _3-12 Heterocycloalkyl of (A), C _3-12 Bicycloalkyl of, C _3-12 Each occurrence of heterobicycloalkyl of (A) is independently optionally deuterium, halogen, OH, CH ₃ 、OCH ₃ 、NH ₂ The substitution forms a spiro ring,

R ₁ and R ₇ Can be connected to form bridged bicyclic rings through alkylene, O and NH,

R ₂ and R ₆ May be linked through an alkylene group to form a bridged bicyclic ring,

R ₂ and R ₇ Can be connected through alkylene and O to form bridged double rings,

R ₄ and R ₆ Can be prepared through NHCH ₂ Is NH is ₂ Substituted C _3-12 The naphthenic base of the benzene ring is connected into a thick double ring,

each a, b, c, d is independently selected at each occurrence from 0, 1;

in some embodiments, the compound of (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, described above, wherein each is

Independently at each occurrence is selected from

And each is

X of (2) ₁ 、X ₂ 、X ₃ 、X ₅ 、X ₆ 、X ₇ Independently at each occurrence is selected from C optionally substituted with 1,2, 3, 4, 5 or 6R ₉ Substituted or unsubstituted;

each R ₉ Independently at each occurrence, selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OC _1-6 Alkyl, -SC _1-6 Alkyl, -NHC _1-6 Alkyl, -N (C) _1-6 Alkyl) (C _1-6 Alkyl), CONH ₂ 、COOH；

In some embodiments, the compound of (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, described above, wherein,

selected from the following structures:

in some embodiments, wherein Ar ₁ Independently at each occurrence, is selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-or 10-membered heteroaryl, 3-to 10-membered cycloalkyl, 5-to 10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl at each occurrenceIndependently at each occurrence, comprises 1,2, 3 or 4 heteroatoms selected from N, O, or S; each Ar ₁ Optionally at each occurrence independently by 1,2, 3, 4, 5 or 6R ₁₉ Substituted or unsubstituted;

each Ar ₂ Independently at each occurrence selected from H, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently at each occurrence containing 1,2, 3 or 4 heteroatoms selected from N, O, or S; each Ar ₂ Optionally at each occurrence independently by 1,2, 3, 4, 5 or 6R ₁₉ Substituted or unsubstituted;

each R ₁₀ And R ₁₁ Independently at each occurrence is selected from hydrogen, deuterium or-C _1-6 Alkyl radical, each R ₁₀ And R ₁₁ Independently optionallyBy 1,2, 3, 4, 5 or 6R ₁₉ Substituted or unsubstituted; or R ₁₀ And R ₁₁ Together with the N atom to which they are both attached form a 3-10 membered heterocyclic ring, which 3-10 membered heterocyclic ring may further comprise 1,2, 3 or 4 substituents selected from N, O, S (= O) or S (= O) ₂ And said 3-10 membered heterocyclic ring is independently optionally substituted with 1,2, 3, 4, 5 or 6R ₂₀ Substituted or unsubstituted;

further preferably, each Ar ₂ -L ₂ -Ar ₁ -L ₁ -is selected from the following structures:

in some embodiments, the compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (ii) or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, optionally in an amount of 0.1-2000mg in the present disclosure, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The disclosure also relates to a process for preparing the pharmaceutical composition, which comprises mixing a compound of formula (ii) or a tautomer, mesomer, racemate, enantiomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a compound of formula (ii) or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier, diluent or excipient.

The disclosure further relates to the use of a compound of formula (ii) or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, for the preparation of a SHP2 inhibitor.

The disclosure further relates to the use of a compound of formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a disease or disorder mediated by SHP2 activity.

The disclosure further relates to the use of a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, as a SHP2 inhibitor, in the manufacture of a medicament for the prevention and/or treatment of tumors or cancers.

The disclosure further relates to a use of a compound represented by the general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, an atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for preventing or treating noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, pancreatic cancer, head and neck squamous cell carcinoma, gastric cancer, liver cancer, anaplastic large-cell lymphoma, and glioblastoma.

The disclosure further relates to compounds of general formula () or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The disclosure also relates to compounds of formula () or tautomers, mesomers, racemic enantiomers, diastereomers, atropisomers or mixtures thereof, or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same, as SHP2 inhibitors.

The disclosure also relates to a compound represented by the general formula () or a tautomer, a meso-racemate, an enantiomer, a diastereomer, an atropisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as an SHP2 inhibitor for preventing and/or treating tumors or cancers.

The present disclosure also relates to a method for the therapeutic prevention and/or treatment of tumors or cancers, comprising administering to a patient in need thereof a therapeutically effective dose of a compound of formula (i) as a SHP2 inhibitor, or its tautomeric mesomer, racemate, enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as a tablet lozenge, troche, aqueous or oil suspension, dispersible powder or granule, emulsion, hard or soft capsule, or syrup or dosage form may be prepared as any method known in the art for the preparation of pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants and preservatives to provide a pleasant and palatable pharmaceutical preparation, and the tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients for mixing and preparing the tablet. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an anti-hydrogenation agent.

The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion where the oily phase may be a vegetable oil, or a mineral oil or mixtures thereof, suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. Sterile injectable preparations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in the oil phase, the injection or microemulsion may be injected into the bloodstream of a patient by local bolus injection, or the solution and microemulsion may be administered, preferably, in such a manner as to maintain a constant circulating concentration of the compound of the present disclosure. To maintain such a constant concentration, a continuous intravenous delivery device may be used an example of such a device is an intravenous pump model Deltec CADD-plus. TM.5400.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The compositions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents such as those described above, or sterile injectable preparations may be prepared as sterile injectable solutions or suspensions in a parenterally acceptable non-toxic diluent or solvent, or sterile fixed oils may conveniently be employed as the solvent or suspending medium, for which purpose any of the fixed oils may be suitably compounded or otherwise employed in the preparation of injectables.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

As is well known to those skilled in the art, the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound employed, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as the mode of treatment, the daily amount of compound (II) or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Certain chemical terms

Unless stated to the contrary, the following terms are used in the specification and claims.

Has the following meanings and is used herein in the manner of _x-y "denotes the range of the number of carbon atoms, wherein x and y are each an integer, e.g. C _3-8 Cycloalkyl denotes cycloalkyl having 3 to 8 carbon atoms, i.e. cycloalkyl having 3, 4, 5, 6,7 or 8 carbon atoms. It is also understood that "C" is _3-8 "also includes any subrange therein, e.g. C _3-7 、C _3-6 、C _4-7 、C _4-6 、C _5-6 And so on.

"alkyl" refers to a straight or branched chain hydrocarbyl group containing 1 to 20 carbon atoms, e.g., 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, and 2-ethylbutyl. The alkyl group may be substituted or unsubstituted.

"alkenyl" refers to a straight or branched chain hydrocarbyl group containing at least one carbon-carbon double bond and typically 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1, 4-pentadienyl, and 1, 4-butadienyl. The alkenyl group may be substituted or unsubstituted.

"alkynyl" refers to a straight or branched chain hydrocarbyl group containing at least one carbon-carbon triple bond and typically 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl. The alkynyl group may be substituted or unsubstituted.

"cycloalkyl" refers to a saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocyclic and typically contain 3 to 7 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups can alternatively be fused together in two or three rings, such as decahydronaphthyl, which can be substituted or unsubstituted.

"Heterocyclyl", "heterocycloalkyl", "heterocycle" refers to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specified, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused, spiro or bridged ring systems, the nitrogen, carbon or sulfur of the heterocyclyl group may optionally be oxidized, the nitrogen atom may optionally be quaternized, and the heterocyclyl group may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule through a single bond via a carbon or heteroatom in the ring. The heterocyclic group containing fused rings may contain one or more aromatic or heteroaromatic rings, provided that the atoms on the non-aromatic ring are attached to the rest of the molecule. For purposes of this application, a heterocyclyl group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like.

"Spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group having one atom (called spiro atom) in common between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated electronic system, preferably 6 to 14, more preferably 7 to 10. The spirocycloalkyl group is classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclic group. Non-limiting examples of spiroheterocyclyl radicals include:

"fused heterocyclyl" means a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

"aryl" or "aryl" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.

"heteroaryl" or "heteroaryl" refers to a 5-16 membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, at least one aromatic ring. Unless otherwise specified, heteroaryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may contain fused or bridged ring systems, provided that the point of attachment to the rest of the molecule is an aromatic ring atom, which may be selectively oxidized at nitrogen, carbon and sulfur atoms, and which may optionally be quaternized. For the purposes of the present invention, heteroaryl groups are preferably stable 4-11 membered monocyclic aromatic rings containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-8 membered monocyclic aromatic rings containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxolyl, benzofuranonyl, benzofuranyl, benzonaphthofuranyl, benzopyranonyl, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, furanyl, imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quininyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, and the like. In the present application, heteroaryl is preferably 5-8 membered heteroaryl comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridyl, pyrimidinyl, thiazolyl. The heteroaryl group may be substituted or unsubstituted.

"halogen" means fluorine, chlorine, bromine or iodine.

"hydroxy" means-OH, and "amino" means-NH ₂ "amido" means-NHCO-, "cyano" means-CN, "nitro" means-CN, "isocyano" means-NC and "trifluoromethyl" means-CF ₃ 。

The term "heteroatom" or "hetero", as used herein alone or as part of another ingredient, refers to atoms other than carbon and hydrogen, and is independently selected from, but not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, and in embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different.

The terms "fused" or "fused ring" as used herein, alone or in combination, refer to a cyclic structure in which two or more rings share one or more bonds.

The term "spiro" or "spirocyclic" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

"optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes where the event or circumstance occurs or does not occur-for example, "heterocyclic group optionally substituted with alkyl" means that alkyl may, but need not, be present, and that the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.

"substituted" means that one or more atoms, preferably 5, more preferably 1 to 3 atoms, in a group are independently substituted with a corresponding number of substituents. It goes without saying that the skilled person in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort, when the substituents are in their possible chemical positions. For example, having a free amine or hydroxyl group may be unstable in combination with a carbon atom having an unsaturated (e.g., olefinic) bond. Such substituents include, but are not limited to, hydroxy, amine, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl groups, and the like.

"pharmaceutical composition" refers to a composition containing one or more compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof, and other ingredients such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote administration to the organism, facilitate absorption of the active ingredient and further exert biological activity.

"isomers" refer to compounds having the same molecular formula but differing in the nature or order of their bonding of atoms or the spatial arrangement of their atoms, referred to as "isomers", and isomers differing in the spatial arrangement of their atoms, referred to as "stereoisomers". Stereoisomers include optical isomers, geometric isomers and conformational isomers. The compounds of the present invention may exist in the form of optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are either in the "R" or "S" configuration. Optical isomers, including enantiomers and diastereomers, and methods of preparing and separating optical isomers are known in the art.

Geometric isomers may also exist for the compounds of the present invention. The present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as either the Z or E configuration, substituents around cycloalkyl or heterocyclic rings are designated as either the cis or trans configuration.

The compounds of the invention may also exhibit tautomerism, such as keto-enol tautomerism.

It is to be understood that the present invention includes any tautomeric or stereoisomeric form and mixtures thereof, and is not to be limited solely to any one tautomeric or stereoisomeric form employed in the nomenclature or chemical structure of the compounds.

"isotopes" are all isotopes of atoms occurring in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as but not limited to ² H、 ³ H、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and ³⁶ and (4) Cl. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labeled reagent in place of a non-isotopically-labeled reagent. Such compounds have a variety of potential uses, for example, as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to favorably alter biological, pharmacological or pharmacokinetic properties.

By "prodrug" is meant that the compounds of the present invention can be administered in the form of a prodrug. Prodrugs refer to derivatives that are converted to the biologically active compounds of the present invention under physiological conditions in vivo, e.g., by oxidation, reduction, hydrolysis, and the like, each of which utilizes or proceeds without the participation of an enzyme. Examples of prodrugs are the following compounds: compounds in which the amine group in the compounds of the invention is acylated, alkylated or phosphorylated, for example eicosanoylamino, propylaminoylamino, pivaloyloxymethylamino, or in which the hydroxyl group is acylated, alkylated, phosphorylated or converted to a borate, for example acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy, propylaminoyloxy, or in which the carboxyl group is esterified or amidated, or in which the sulfhydryl group forms a disulfide bridge with a carrier molecule, for example a peptide, which selectively delivers a drug to the target and/or to the cytosol of the cell, can be prepared from the compounds of the invention according to well-known methods.

"pharmaceutically acceptable salt" or "pharmaceutically acceptable" means made from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also includes their corresponding pharmaceutically acceptable salts. The compounds of the invention which contain acidic groups can therefore be present in salt form and can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium or salts with amines or organic amines, such as primary, secondary, tertiary, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purines, piperazine, piperidine, choline, caffeine, and the like, with particularly preferred organic bases being isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The compounds of the invention containing basic groups can be present in the form of salts and can be used according to the invention in the form of their addition to inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of the invention contain both acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, internal or betaine salts. The salts are obtained by conventional methods known to the person skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.

Thus, when reference is made in this application to "a compound", "a compound of the invention" or "a compound of the invention", all said compound forms are included, such as prodrugs, stable isotopic derivatives, pharmaceutically acceptable salts, isomers, meso-forms, racemates, enantiomers, diastereomers and mixtures thereof.

In this context, the term "tumor" includes both benign tumors and malignant tumors (e.g., cancers).

The term "cancer" as used herein includes various malignancies in which Bruton's tyrosine kinase is involved, including, but not limited to, non-small cell lung cancer, esophageal cancer, melanoma, striated muscle garnet, cell carcinoma, multiple myeloma, breast cancer ovarian cancer, endometrial cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer and liver cancer (e.g., hepatocellular carcinoma), more specifically liver cancer, gastric cancer and bladder cancer.

The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.

The term "polymorph" or "polymorph" as used herein means that the compounds of the present invention have multiple crystal lattice forms, some of the compounds of the present invention may have more than one crystal form, and the present invention encompasses all polymorphic forms or mixtures thereof.

Intermediate compounds of the present invention and polymorphs thereof are also within the scope of the present invention.

Crystallization often results in a solvate of a compound of the present invention, and the term "solvate" as used herein refers to an association of one or more molecules of a compound of the present invention and one or more molecules of a solvent.

The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent may be used. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases the compounds of the invention may also be present only occasionally as water or as a mixture of water with some other solvent the compounds of the invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.

As used herein, the term "acceptable" in reference to a formulation, composition or ingredient means that there is no lasting deleterious effect on the overall health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.

"pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonizing agents, solvents, or emulsifiers that have been approved by the relevant governmental authorities for use in humans and domestic animals.

As used herein, the term "subject," "patient," "subject" or "individual" refers to an individual having a disease, disorder or condition, and the like, including mammals and non-mammals, examples of which include, but are not limited to, any member of the class mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment related to the methods and compositions provided herein, the mammal is a human.

The term "treatment" as used herein refers to the treatment of a disease condition associated with a mammal, particularly a human, and includes

(i) Preventing the development of a disease or condition in a mammal, particularly a mammal that has been previously exposed to the disease or condition but has not been diagnosed with the disease or condition;

(ii) Inhibiting the disease or disorder, i.e., controlling its development;

(iii) Relieving the disease or condition, i.e., slowing the regression of the disease or condition;

(iv) Relieving symptoms caused by the disease or disorder.

The terms "disease" and "condition" as used herein may be used interchangeably and may have different meanings, as certain specific diseases or conditions have no known causative agent (and therefore the cause of the disease is not yet clear) and therefore are not considered as a disease but can be considered as an unwanted condition or syndrome, with more or less specific symptoms being confirmed by clinical researchers.

The terms "administering," "administration," "administering," and the like as used herein refer to methods that are capable of delivering a compound or composition to a desired site for a biological action. Including, but not limited to, oral, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

Detailed description of the invention

The invention also provides a method for preparing the compound. The preparation of the compounds of the general formula (I) according to the invention can be carried out by the following exemplary methods and examples, which should not be taken in any way as a limitation of the scope of the invention. The compounds of the invention can also be synthesized using synthetic techniques known to those skilled in the art, or a combination of methods known in the art and those described herein. The product of each step is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatography, and the like. The starting materials and chemical reagents required for the synthesis can be routinely synthesized or purchased according to the literature (reaxys).

Unless otherwise indicated, temperatures are in degrees celsius. Reagents were purchased from commercial suppliers such as Chemblocks Inc, astatech Inc, or mcelin, and these reagents were used directly without further purification unless otherwise stated.

Unless otherwise specified, the following reactions are carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or gas, or using a drying tube; glassware was dried and/or heat dried.

Unless otherwise stated, column chromatography purification used 200-300 mesh silica gel from Qingdao oceanic plant; preparation of thin-layer chromatography silica gel precast slab (HSGF 254) produced by Nicotiana chemical industry research institute; MS was measured using a Therno LCD flash model (ESI) liquid chromatography-mass spectrometer.

Nuclear magnetic data (1 HNMR) Using a Bruker Avance-400MHz or Varian Oxford-400Hz nuclear magnetic instrument, the nuclear magnetic data was performed using CDCl as the solvent ₃ 、CD ₃ OD、D ₂ O、DMSO-d ₆ Etc. based on tetramethylsilane (0.000 ppm) or based on residual solvent (CDCl) _3: 7.26ppm；CD ₃ OD:3.31ppm；D ₂ O:4.79ppm；DMSO-d ₆ 2.50 ppm) when indicating the diversity of the peak shapes, the following abbreviations indicate the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). If the coupling constant is given, it is given in Hertz (Hz).

Preparation of intermediate 1-methyl-3- (tributylstannyl) -1H-pyrazole

The compound 1-methyl-3-bromopyrazole (5 g, 31.25mmol) was dissolved in 80mL of toluene, hexa-n-butylditin (18.05g, 31.25mmol) and tetratriphenylphosphine palladium (1.79g, 1.56mmol) were added, and the reaction was stirred at 120 ℃ for 5 hours. Cooled to room temperature, and the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound 1-methyl-3- (tributylstannyl) -1H-pyrazole (2.9 g, 25% yield).

Preparation of intermediate 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol

The compound 3-fluoro-2-chloroaniline (5 g, 34.35mmol) was dissolved in 80mL of N, N-dimethylformamide, and tert-butylmercaptan (9.29g, 103mmol) and cesium carbonate (16.79g, 51.53mmol) were added thereto, and the reaction was stirred at 120 ℃ for 24 hours. After cooling to room temperature, the reaction mixture was poured into 150mL of a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound 3- (tert-butylmercapto) -2-chloroaniline (5.85 g, yield 79%). LC/MS (ESI) m/z =216.1[ 2 ] M + H] ⁺ .

The compound 3- (tert-butylmercapto) -2-chloroaniline (5 g, 23.25mmol) was dissolved in 15mL of concentrated hydrochloric acid, 40mL of an aqueous solution of sodium nitrite (1.25g, 26.3mmol) was added dropwise at-5 ℃ and stirred for 1 hour, 40mL of an aqueous solution of potassium iodide (5.4 g,46.5 mmol) was added dropwise at-5 ℃ and stirred for reaction for 30 minutes. The reaction solution was extracted with ethyl acetate, and the organic phase obtained was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound 3- (tert-butylmercapto) -2-chloro-1-iodobenzene (4.93 g, 65% yield). LC/MS (ESI) m/z =326.9[ m + H ]] ⁺ .

The compound 1-methyl-3- (tributylstannyl) -1H-pyrazole (2g, 5.39mmol) was dissolved in 50mL of xylene, and the compound 3- (tert-butylmercapto) -2-chloro-1-iodobenzene (1.76g, 5.39mmol) and tetratriphenylphosphine palladium (312mg, 0.27mmol) were added, and the reaction was stirred at reflux for 2 hours. Cooled to room temperature, and the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound (3- (3- (tert-butylmercapto) -2-chlorobenzene) -1-methyl-1H-pyrazole (1.14 g, 75% yield). LC/MS (ESI) m/z =281.1[ 2M + H ]] ⁺ .

Compound 3- (3- (tert-butylmercapto) -2-chlorobenzene) -1-methyl-1H-pyrazole (1.12g, 4 mmol) was dissolved in toluene 25mL, and anhydrous aluminum trichloride (2.13g, 16mmol) was added, and the reaction was stirred at room temperature for 1 hour under nitrogen protection. Adding ice water for quenching, and extracting by ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Crude 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (0.89 g, 99% yield) was obtained and used directly in the next reaction. LC/MS (ESI) m/z =225.0[ m + H ]] ⁺ .

Preparation of intermediate 3- (1-ethyl-1H-pyrazol-3-yl) -2-chloro-thiophenol

The compound 3- (1-ethyl-1H-pyrazol-3-yl) -2-chloro-thiophenol was obtained by a similar preparation method to that of the intermediate 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (starting material was changed to 3-bromo-1-ethylpyrazole). LC/MS (ESI) m/z =240.0[ m + H ]] ⁺ .

Preparation of intermediate 3- (1-isopropyl-1H-pyrazol-3-yl) -2-chloro-thiophenol

The compound 3- (1-isopropyl-1H-pyrazol-3-yl) -2-chloro-thiophenol was obtained by a similar preparation method to that of the intermediate 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (starting material was changed to 3-bromo-1-isopropylpyrazole). LC/MS (ESI) m/z =254.0[ 2[ M ] +H] ⁺ .

Preparation of intermediate 3- (pyrimidin-5-yl) -2-chloro-thiophenol

With the intermediate 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenolA similar preparation (starting material was changed to 3-bromo-1-isopropylpyrazole) gave the compound 3- (pyrimidin-5-yl) -2-chloro-thiophenol. LC/MS (ESI) m/z =224.0[ m + H ]] ⁺ .

Preparation of intermediate 3- (pyrazin-2-yl) -2-chloro-thiophenol

The compound 3- (pyrazin-2-yl) -2-chloro-thiophenol was obtained using a preparation method similar to that of the intermediate 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (starting material was changed to 3-bromo-1-isopropylpyrazole). LC/MS (ESI) m/z =224.0[ m + H ]] ⁺ .

Preparation of intermediate 3- (pyridin-3-yl) -2-chloro-thiophenol

The compound 3- (pyridin-2-yl) -2-chloro-thiophenol was obtained using a preparation similar to that of the intermediate 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (starting material was changed to 3-bromo-1-isopropylpyrazole). LC/MS (ESI) m/z =222.0[ M + H ]] ⁺ .

Preparation of intermediate 3- (pyrimidin-4-yl) -2-chloro-thiophenol

The compound 3- (pyrimidin-4-yl) -2-chloro-thiophenol was obtained using a preparation method similar to that for the intermediate 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (starting material was changed to 3-bromo-1-isopropylpyrazole). LC/MS (ESI) m/z =224.0[ m + H ]] ⁺ .

Preparation of intermediate ethyl 2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidine-3-carboxylate

Compound 4c (4.64g, 20mmol) and 2-aminopyridine (0.94g, 10mmol) were dissolved in 40mL of xylene, and the reaction mixture was heated to 120 ℃ and stirred for 16 hours. Cooling to room temperature, filtering, washing the filter cake with methanol for 3 times, and drying to obtain the compound 2-hydroxy-4-oxo-pyridine [1,2-a ]]And pyrimidine-3-carboxylic acid ethyl ester (0.58 g, 25% yield). LC/MS (ESI) m/z =235.1[ 2[ M ] +H] ⁺ .

Under the protection of nitrogen, the compound 2-hydroxy-4-oxo-pyridine [1,2-a ]]Ethyl pyrimidine-3-carboxylate (468mg, 2mmol) was dissolved in 4mL of methanol, and then palladium on carbon (40 mg) was added thereto and the mixture was replaced with hydrogen gas for 3 times, followed by stirring at room temperature for reaction for 2 hours. Filtering, concentrating under reduced pressure to obtain 2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ]]And pyrimidine-3-carboxylic acid ethyl ester (452 mg, 95% yield). LC/MS (ESI) m/z =239.1[ 2 ] M + H] ⁺ .

Preparation of intermediate 3-amino-2-chloro-thiophenol

Dissolving the compound 3- (3- (tert-butylmercapto) -2-chloroaniline (10g, 46.4mmol) in 100mL concentrated hydrochloric acid, heating to 55 ℃, stirring, reacting overnight, cooling to room temperature, quenching sodium bicarbonate to neutrality, extracting the aqueous phase with ethyl acetate, washing the obtained organic phase with saturated saline, drying with anhydrous sodium sulfate, evaporating the organic phase under reduced pressure, and purifying the residue by column chromatography to obtain the compound 3-amino-2-chloro-thiophenol (4.9 g, yield 66%). LC/MS (ESI): m/z =160.0[ M + H ],] ⁺ .

preparation of intermediate N- (2-chloro-3-mercaptophenyl) pyrimidine-2-carboxamide

Pyrimidine-2-carboxylic acid (620mg, 5mmol) was added to 10mL of thionyl chloride, stirred under reflux for 2 hours, and concentrated under reduced pressure to give an acid chloride, and 15mL of methylene chloride, pyridine (593mg, 7.5mmol), 3- (3- (tert-butylmercapto) -2-chloroaniline (539mg, 2.5mmol), 4-dimethylaminopyridine (153 mg,1.25 mmol), the reaction was stirred at room temperature for 2 hours. Adding water for quenching, extracting by dichloromethane, washing the obtained organic phase by saturated saline solution, drying by anhydrous sodium sulfate, and evaporating the organic phase by decompression. The residue was purified by column chromatography to give the compound N- (2-chloro-3- (3- (tert-butylmercapto) phenyl) pyrimidine-2-carboxamide (627 mg, yield 78%). LC/MS (ESI) m/z =322.1[ M + H ] +] ⁺ .

Dissolving a compound N- (2-chloro-3- (3- (tert-butylmercapto) phenyl) pyrimidine-2-formamide (578mg, 1.8mmol) in 30mL of concentrated hydrochloric acid, reacting at 50 ℃ for 2 hours, cooling to room temperature, quenching sodium bicarbonate to neutrality, extracting an aqueous phase with ethyl acetate, washing an obtained organic phase with saturated saline, drying over anhydrous sodium sulfate, evaporating the organic phase under reduced pressure, and purifying the residue by column chromatography to obtain the compound N- (2-chloro-3-mercaptophenyl) pyrimidine-2-formamide (0.27 g, with the yield of 56%). LC/MS (ESI): m/z =266.0[ M + ]] ⁺ .

Preparation of intermediate N- (2-chloro-3-mercaptophenyl) pyrimidine-4-carboxamide

The compound N- (2-chloro-3-mercaptophenyl) pyrimidine-4-carboxamide was obtained by a similar preparation method to that of the intermediate N- (2-chloro-3-mercaptophenyl) pyrimidine-2-carboxamide (starting material was changed to pyrimidine-4-carboxylic acid). LC/MS (ESI) m/z =266.0[ m + H ]] ⁺ .

The compound N- (2-chloro-3-mercaptophenyl) pyrazine-2-carboxamide is obtained by a similar preparation method (the raw material is replaced by pyrazine-2-carboxylic acid) as the intermediate N- (2-chloro-3-mercaptophenyl) pyrimidine-2-carboxamide. LC/MS (ESI) m/z =266.0[ m + H ]] ⁺ .

Preparation of intermediate N- (2-chloro-3-mercaptophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide

The compound 3- (3- (tert-butylmercapto) -2-chloroaniline (1.08g, 5 mmol) and the compound 2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ]]Ethyl pyrimidine-3-carboxylate (1.43g, 6 mmol) was dissolved in 20mL of chlorobenzene, and the reaction mixture was stirred under reflux for 3 hours. Cooling to room temperature, filtering, and drying to obtain the compound N- (3- (tert-butylmercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ]]And pyrimidine-3-carboxamide (1.18 g, 58% yield). LC/MS (ESI) m/z =408.1[ 2 ] M + H] ⁺ .

The compound N- (3- (tert-butylmercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ]]Pyrimidine-3-carboxamide (1.02g, 2.5 mmol) was dissolved in 10mL of concentrated hydrochloric acid, and the reaction was stirred at 50 ℃ for 3 hours. Cool to room temperature, quench sodium bicarbonate to neutral, extract the aqueous phase with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound N- (2-chloro-3-mercaptophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ]]And pyrimidine-3-carboxamide (0.57 g, 65% yield). LC/MS (ESI) m/z =353.0[ 2[ M ] +H] ⁺ .

Preparation of intermediate 3- (1-methylpyrazole-4-oxy) -2-chloro-thiophenol

The compound 1-methyl-1H-pyrazol-3 (2H) -one (0.49g, 5 mmol) was dissolved in 8mL of N, N-dimethylformamide, and 3- (tert-butylmercapto) -2-chloro-1-iodobenzene (1.79g, 5.5 mmol) and cesium carbonate (3.26g, 10 mmol) were added thereto, and the mixture was heated to 50 ℃ and stirred for reaction for 6 hours. Cooled to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give 3- (3- (tert-butylmercapto) -2-chlorophenoxy) -1-carbaldehydeYl-1H-pyrazole (1.11 g, 75% yield). LC/MS (ESI) m/z =297.1[ m + H ]] ⁺ .

The compound 3- (3- (tert-butylmercapto) -2-chlorophenoxy) -1-methyl-1H-pyrazole (890mg, 3mmol) was dissolved in 30mL of concentrated hydrochloric acid and reacted at 50 ℃ for 2 hours. Cool to room temperature, quench sodium bicarbonate to neutral, and extract the aqueous phase with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound 3- (1-methylpyrazol-4-oxy) -2-chloro-thiophenol (440 mg, yield 61%). LC/MS (ESI) m/z =241.0[ m + H ]] ⁺ .

Preparation of intermediate 2, 6-dichloropyridyl [3,2-d ] pyrimidine

The compound 3-amino-6-chloropyridinal (1.57g, 10 mmol) was dissolved in 15mL of urea, and the reaction was stirred at 130 ℃ for 2 hours. Cooling to room temperature, filtering, washing the filter cake with water, and drying to obtain the compound 2-hydroxy-6-chloropyridine [3,2-d]And pyrimidine (1.63 g, 90% yield). LC/MS (ESI) m/z =182.0[ M + H ]] ⁺ .

Reacting the compound 2-hydroxy-6-chloropyridine [3,2-d ]]And pyrimidine (0.91g, 5 mmol) is dissolved in 20mL of phosphorus oxychloride, and the temperature is raised to 105 ℃ to be stirred for reaction for 3 hours. Cooling to room temperature, removing most of the solvent under reduced pressure, pouring the residue into ice water, extracting with dichloromethane, washing the resulting organic phase with saturated sodium bicarbonate solution and saturated brine, drying over anhydrous sodium sulfate, and evaporating the organic phase under reduced pressure. Purifying the residue by column chromatography to obtain 2, 6-dichloropyridine [3,2-d ] as compound]And pyrimidine (0.62 g, 62% yield). LC/MS (ESI) m/z =200.0[ m + H ]] ⁺ .

Preparation of intermediate 2, 6-dichloropyridyl [2,3-b ] pyrazine

Reacting the compound 2-hydroxy-6-chloropyridine [3,2-d ]]And a pyrazine (0.91 g,5 mmol) was dissolved in 10mL of toluene, and phosphorus oxychloride (5.1mL, 55mmol) was added and the reaction was stirred at reflux for 24 hours. The mixture was cooled to room temperature, the residue was poured into ice water, extracted with dichloromethane, and the resulting organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. Purifying the residue by column chromatography to obtain 2, 6-dichloropyridine [2,3-b ] compound]And pyrazine (0.85 g, 85% yield). LC/MS (ESI) m/z =200.0[ m + H ]] ⁺ .

Preparation of intermediate 2, 6-dichloropteridine

With 2, 6-dichloropyridine [3,2-d ] as intermediate]The compound 2, 6-dichloropteridine is obtained by a similar preparation method of the pyrimidine (the raw material is changed into 3-amino-6-chloropyrazine-2-aldehyde). LC/MS (ESI) m/z =201.0[ m + H ]] ⁺ .

Example 1

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (1-methyl-1H-pyrazol-3-yl) phenyl) mercapto) pteridin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (1)

The compound 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (674mg, 3mmol) was dissolved in 8mL of N, N-dimethylacetamide, 2, 6-dichloropteridine (720mg, 3.6 mmol), potassium hydroxide (336mg, 6.0 mmol) and cuprous oxide (215mg, 1.5 mmol) were added thereto, nitrogen gas was replaced 3 times, and the mixture was reacted at 60 ℃ for 8 hours with stirring. Cooled to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate. The resulting organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and vacuum evaporated to dryness to give intermediate 6-chloro- (2- ((2-chloro-3- (1-methyl-1H-pyrazol-3-yl) phenyl) mercapto) pteridine (619 mg, yield 53%). LC/MS (ESI): m/z =389.0[ M + H ], (+)] ⁺ .

The compound 6-chloro- (2- ((2-chloro-3- (1-methyl-1H-pyrazol-3-yl) phenyl) mercapto) pteridine (584mg, 1.5mmol) was dissolved10mL of N, N-dimethylformamide was added with (3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decane dihydrochloride (438mg, 1.8mmol), cesium carbonate (1.95g, 6.0mmol), and the reaction at 120 ℃ for 12 hours with stirring. Cooled to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the objective product 1 (282 mg, yield 36%). ¹ HNMR(400MHz,DMSO-d ₆ )δ:8.41(s,1H),8.34(s,1H),7.78(d,1H),7.51(d,1H),7.23(t,1H),6.84(d,1H),6.60(d,1H),4.13-4.09(m,1H),3.95-3.45(m,7H),3.32-3.25(m,2H),2.90(d,1H),1.75-1.30(m,6H),1.14(d,3H)；LC/MS(ESI):m/z＝523.2[M+H] ⁺ .

Example 2

Preparation of (3S, 4S) -8- (6- ((2-chloro-3- (1-methyl-1H-pyrazol-3-yl) phenyl) mercapto) pteridin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (2)

2, 6-dichloropteridine (0.72g, 3.6 mmol) was dissolved in 10mL of methylene chloride and (3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] was added]Decane dihydrochloride (0.73g, 3mmol), triethylamine (0.91g, 9mmol), and the reaction was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound (3S, 4S) -8- (6-chloropteridin-2-yl) -3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-4-amine (0.65 g, 65% yield). LC/MS (ESI) m/z =335.1[ m + H ]] ⁺ .

The compound (3S, 4S) -8- (6-chloropteridine-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decane-4-amine (502mg, 1.5 mmol) was dissolved in 8mL of 1, 4-dioxane, and the compounds 3- (1-methyl-1H-pyrazol-3-yl) -2-chloro-thiophenol (405mg, 1.8 mmol), potassium tert-butoxide (335mg, 3.0 mmol) and cuprous iodide (29mg, 0.15mmol) were added thereto, nitrogen gas was replaced 3 times, and the reaction was refluxed for 16 hours with stirring. Cooling to room temperature, passing the reaction solution through a silica gel short column, and adding ethyl acetateAnd (5) leaching, decompressing and evaporating to dryness. The residue was purified by column chromatography to give the objective product 2 (377 mg, yield 48%). ¹ HNMR(400MHz,DMSO-d6)δ:8.71(s,1H),8.43(s,1H),7.78(d,1H),7.51(d,1H),7.23(t,1H),6.85(d,1H),6.58(d,1H),4.13-4.09(m,1H),3.95-3.44(m,7H),3.34-3.25(m,2H),2.92(d,1H),1.75-1.31(m,6H),1.15(d,3H)；LC/MS(ESI):m/z＝523.2[M+H] ⁺ .

Example 3

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (1-methyl-1H-pyrazol-3-yl) phenyl) mercapto) pyridine [3,2-d ] opyrimidin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (3)

Compound 3 (328 mg, 42% yield, which is the final step yield, the same applies below) was obtained in a similar manner to example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.42(s,1H),7.93(d,1H),7.78(d,1H),7.51(d,1H),7.23(t,1H),6.88-6.75(m,2H),6.59(d,1H),4.13-4.09(m,1H),3.94-3.45(m,7H),3.31-3.25(m,2H),2.91(d,1H),1.75-1.30(m,6H),1.15(d,3H)；LC/MS(ESI):m/z＝522.2[M+H] ⁺ .

Example 4

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (1-ethyl-1H-pyrazol-3-yl) phenyl) mercapto) pteridin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (4)

Compound 4 (322 mg, 40% yield) was obtained in a similar manner to example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.42(s,1H),8.34(s,1H),7.75(d,1H),7.51(d,1H),7.23(t,1H),6.83(d,1H),6.56(d,1H),4.13-4.09(m,1H),3.95-3.44(m,6H),3.32-3.25(m,2H),2.90(d,1H),1.73-1.31(m,6H),1.28(t,3H),1.13(d,3H)；LC/MS(ESI):m/z＝537.2[M+H] ⁺ .

Example 5

Preparation of (3S, 4S) -8- (6- ((2-chloro-3- (1-ethyl-1H-pyrazol-3-yl) phenyl) mercapto) pteridin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (5)

Compound 5 (362 mg, 45% yield) was obtained in a similar manner to example 2. LC/MS (ESI) m/z =537.2[ m + H ]] ⁺ .

Example 6

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (1-ethyl-1H-pyrazol-3-yl) phenyl) mercapto) pyridine [3,2-d ] opyrimidin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (6)

Compound 6 (305 mg, 38% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z =536.2[ m + H ]] ⁺ .

Example 7

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (1-isopropyl-1H-pyrazol-3-yl) phenyl) mercapto) pteridin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (7)

Compound 7 (305 mg, 37% yield) was obtained in a similar manner to example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.42(s,1H),8.34(s,1H),7.76(s,1H),7.51(d,1H),7.23(t,1H),6.83(d,1H),6.55(d,1H),4.14-4.07(m,2H),3.93-3.45(m,4H),3.32-3.25(m,2H),2.90(d,1H),1.73-1.30(m,12H),1.14(d,3H)；LC/MS(ESI):m/z＝551.2[M+H] ⁺ .

Example 8

Preparation of (3S, 4S) -8- (6- ((2-chloro-3- (1-isopropyl-1H-pyrazol-3-yl) phenyl) mercapto) pteridin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (8)

Compound 8 (380 mg, 46% yield) was obtained in a similar manner to example 2. LC/MS (ESI) m/z =551.2[ m + H ]] ⁺ .

Example 9

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (1-isopropyl-1H-pyrazol-3-yl) phenyl) mercapto) pyridine [3,2-d ] opyrimidin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (9)

Compound 9 (288 mg, 35% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z =550.2[ m + H ]] ⁺ .

Example 10

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (pyrazin-2-yl) phenyl) mercapto) pteridin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (10)

Compound 10 (273 mg, 35% yield) was obtained in a similar manner to example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.81(s,1H),8.75(s,2H),8.43(s,1H),8.34(s,1H),7.51(d,1H),7.21(t,1H),6.86(d,1H),4.13-4.09(m,1H),3.94-3.75(m,2H),3.65(d,1H),3.47(d,1H),3.32-3.25(m,2H),2.90(d,1H),1.75-1.33(m,6H),1.14(d,3H)；LC/MS(ESI):m/z＝521.2[M+H] ⁺ .

Example 11

Preparation of (3S, 4S) -8- (6- ((2-chloro-3- (pyrazin-2-yl) phenyl) mercapto) pteridin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (11)

Compound 11 (328 mg, 42% yield) was obtained in a similar manner to example 2. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.82-8.80(m,2H),8.75(s,2H),8.43(s,1H),7.51(d,1H),7.23(t,1H),7.05(d,1H),4.13-4.09(m,1H),3.94-3.43(m,4H),3.32-3.23(m,2H),2.91(d,1H),1.79-1.33(m,6H),1.15(d,3H)；LC/MS(ESI):m/z＝521.2[M+H] ⁺ .

Example 12

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (pyrazin-2-yl) phenyl) mercapto) pyridin [3,2-d ] opyrimidin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (12)

Compound 12 (288 mg, 37% yield) was obtained in a similar manner to example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.81(s,1H),8.75(s,2H),8.43(s,1H),7.91(d,1H),7.51(d,1H),7.21(t,1H),6.86-6.79(m,2H),4.13-4.09(m,1H),3.94-3.75(m,2H),3.65(d,1H),3.47(d,1H),3.32-3.25(m,2H),2.90(d,1H),1.75-1.33(m,6H),1.14(d,3H)；LC/MS(ESI):m/z＝520.2[M+H] ⁺ .

Example 13

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (pyrimidin-4-yl) phenyl) mercapto) pteridin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (13)

Compound 13 (320 mg, 41% yield) was obtained in a similar manner to example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ:9.24(s,1H),8.85(d,1H),8.43(s,1H),8.35(s,1H),8.12(d,1H),7.50(d,1H),7.21(t,1H),6.86(d,1H),4.13-4.09(m,1H),3.94-3.75(m,2H),3.65(d,1H),3.47(d,1H),3.32-3.25(m,2H),2.91(d,1H),1.77-1.33(m,6H),1.14(d,3H)；LC/MS(ESI):m/z＝521.2[M+H] ⁺ .

Example 14

Preparation of (3S, 4S) -8- (6- ((2-chloro-3- (pyrimidin-4-yl) phenyl) mercapto) pteridin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (14)

Compound 14 (295 mg, 37% yield) was obtained in a similar manner to example 2. LC/MS (ESI) m/z =521.2[ m + H ]] ⁺ .

Example 15

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (pyrimidin-4-yl) phenyl) mercapto) pyridin [3,2-d ] opyrimidin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (15)

Compound 15 (350 mg, 45% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z =520.2[ m + H ]] ⁺ .

Example 16

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (pyrimidin-3-yl) phenyl) mercapto) pteridin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (16)

Compound 16 (327 mg, 42% yield) was obtained in a similar manner to example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.87(s,1H),8.71(d,1H),8.34-8.30(m,3H),7.55-7.51(m,2H),7.22(t,1H),7.04(d,1H),4.13-4.08(m,1H),3.94-3.45(m,4H),3.31-3.25(m,2H),2.91(d,1H),1.78-1.31(m,6H),1.15(d,3H)；LC/MS(ESI):m/z＝520.2[M+H] ⁺ .

Example 17

Preparation of (3S, 4S) -8- (6- ((2-chloro-3- (pyrimidin-4-yl) phenyl) mercapto) pteridin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (17)

Compound 17 (273 mg, 35% yield) was obtained in a similar manner to example 2. LC/MS (ESI) m/z =520.2[ m + H ]] ⁺ .

Example 18

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (pyrimidin-4-yl) phenyl) mercapto) pyridin [3,2-d ] opyrimidin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (18)

Compound 18 (295 mg, 38% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z =519.2[ m + H ]] ⁺ .

Example 19

Preparation of N- (3- ((6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pteridin-2-yl) mercapto) -2-chlorophenyl) pyrimidine-4-carboxamide (19)

Compound 19 (320 mg, 41% yield) was obtained in a similar manner to example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ:9.88(s,1H),9.31(s,1H),9.01(d,1H),8.43(s,1H),8.35(s,1H),8.31(s,2H),8.21(d,1H),7.75(d,1H),7.42(t,1H),7.15(d,1H),4.15-4.11(m,1H),3.93-3.45(m,4H),3.33-3.21(m,2H),2.90(d,1H),1.75-1.31(m,6H),1.15(d,3H)；LC/MS(ESI):m/z＝564.2[M+H] ⁺ .

Example 20

Preparation of N- (3- ((2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pteridin-6-yl) mercapto) -2-chlorophenyl) pyrimidine-4-carboxamide (20)

Compound 20 (295 mg, 37% yield) was obtained in a similar manner to example 2. LC/MS (ESI) m/z =564.2[ 2 ], [ M + H ]] ⁺ .

Example 21

Preparation of N- (3- ((6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyridine [3,2-d ] pyrimidin-2-yl) mercapto) -2-chlorophenyl) pyrimidine-4-carboxamide (21)

Compound 21 (350 mg, 45% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z =563.2[ M + H ]] ⁺ .

Example 22

Preparation of N- (3- ((6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pteridin-2-yl) mercapto) -2-chlorophenyl) pyrazine-2-carboxamide (22)

Compound 22 (313 mg, 37% yield) was obtained in a similar manner to example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ:9.70(s,1H),9.51(s,1H),8.81(d,1H),8.55-8.52(m,1H),8.43(s,1H),8.35(s,1H),7.75(d,1H),7.42(t,1H),7.14(d,1H),4.15-4.11(m,1H),3.93-3.45(m,4H),3.33-3.21(m,2H),2.90(d,1H),1.75-1.31(m,6H),1.15(d,3H)；LC/MS(ESI):m/z＝564.2[M+H] ⁺ .

Example 23

Preparation of N- (3- ((2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pteridin-6-yl) mercapto) -2-chlorophenyl) pyrazine-2-carboxamide (23)

Compound 23 (337 mg, 40% yield) was obtained in a similar manner to example 2. LC/MS (ESI):m/z＝564.2[M+H] ⁺ .

Example 24

Preparation of N- (3- ((6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyridine [3,2-d ] pyrimidin-2-yl) mercapto) -2-chlorophenyl) pyrazine-2-carboxamide (24)

Compound 24 (346 mg, 41% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z =563.2[ M + H ]] ⁺ .

Example 25

Preparation of N- (3- ((6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pteridin-2-yl) mercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide (25)

Compound 25 (341 mg, 35% yield) was obtained in a similar manner to example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.3(br s,1H),8.42(s,1H),8.35(s,1H),8.24(s,1H),7.23(s,1H),6.63(d,1H),5.51(br s,3H),4.13-4.10(m,1H),3.93-3.45(m,8H),2.95(d,1H),2.74(s,2H),1.85-1.41(m,8H),1.14(d,3H)；LC/MS(ESI):m/z＝650.2[M+H] ⁺ .

Example 26

Preparation of N- (3- ((2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pteridin-6-yl) mercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide (26)

Compound 26 (389 mg, 40% yield) was obtained in a similar manner to example 2. LC/MS (ESI) m/z =650.2[ m + H ]] ⁺ .

Example 27

Preparation of N- (3- ((6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyridine [3,2-d ] pyrimidin-2-yl) mercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide (27)

Compound 27 (369 mg, 38% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z =649.2[ 2 ] M + H] ⁺ .

Example 28

Preparation of (3S, 4S) -8- (6- ((2-chloro-3- (1-methyl-1H-pyrazol-3-yl) phenyl) mercapto) pyridine [3,2-b ] pyrimidin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (28)

Compound 28 (281 mg, 36% yield) was obtained in a similar manner to example 2. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.43(s,1H),7.96(d,1H),7.78(d,1H),7.49-7.23(m,3H),6.88(d,1H),6.59(d,1H),4.13-3.45(m,8H),3.30-3.25(m,2H),2.91(d,1H),1.75-1.30(m,6H),1.15(d,3H)；LC/MS(ESI):m/z＝522.2[M+H] ⁺ .

Example 29

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (1-methyl-1H-pyrazol-3-yl) phenyl) mercapto) pyridine [2,3-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (29)

Compound 29 (235 mg, 30% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z =522.2[ 2 ], [ M + H ]] ⁺ .

Example 30

Preparation of (3S, 4S) -8- (6- ((2-chloro-3- (1-methyl-1H-pyrazol-3-yl) phenyl) mercapto) pyridine [2,3-b ] pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (30)

Compound 30 (211 mg, 27% yield) was obtained in a similar manner to example 2. LC/MS (ESI) m/z =522.2[ m + H ]] ⁺ .

Example 31

Preparation of (3S, 4S) -8- (6- ((2-chloro-3- (1-methyl-1H-pyrazol-3-yl) hydroxy) phenyl) mercapto) pteridin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (31)

Compound 31 (315 mg, 39% yield) was obtained in a similar manner to example 2. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.43-8.40(m,2H),7.78(d,1H),7.03-6.55(m,4H),4.14-3.45(m,8H),3.32-3.25(m,2H),2.91(d,1H),1.75-1.30(m,6H),1.14(d,3H)；LC/MS(ESI):m/z＝539.2[M+H] ⁺ .

Example 32

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (1-methyl-1H-pyrazol-3-yl) hydroxy) phenyl) mercapto) pteridin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (32)

Compound 32 (331 mg, 41% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z =539.2[ 2 ], [ M + H ]] ⁺ .

Example 33

Preparation of (3S, 4S) -8- (2- ((2-chloro-3- (1-methyl-1H-pyrazol-3-yl) hydroxy) phenyl) mercapto) pyridine [3,2-d ] pyrimidin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (33)

Compound 33 (282 mg, 35% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z =538.2[ m + H ]] ⁺ .

Example 34

Preparation of N- (3- ((2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyridine [3,2-d ] pyrimidin-6-yl) mercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide (34)

Compound 34 (379 mg, 39% yield) was obtained in a similar manner to example 2. ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.1(br s,1H),8.43(s,1H),7.94-7.76(m,2H),7.33-7.24(m,2H),6.67(d,1H),5.52(br s,3H),4.13-4.10(m,1H),3.93-3.45(m,8H),2.93(d,1H),2.71(s,2H),1.83-1.35(m,8H),1.14(d,3H)；LC/MS(ESI):m/z＝649.2[M+H] ⁺ .

Example 35

Preparation of N- (3- ((6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyridine [2,3-b ] pyrazin-2-yl) mercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide (35)

Compound 35 (340 mg, 35% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z =649.2[ m + H ]] ⁺ .

Example 36

Preparation of N- (3- ((2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyridine [2,3-b ] pyrazin-6-yl) mercapto) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide (36)

Compound 36 (315 mg, 33% yield) was obtained in a similar manner to example 2. LC/MS (ESI) m/z =649.2[ m + H ]] ⁺ .

Example 37 bioactivity assay

The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention. SHP2 allosteric inhibition experiment

Determination of SHP-2 kinase Activity inhibition by Compounds

The purpose of this test was to measure the inhibitory ability of compounds on the allosteric activity of the full-length SHP-2 protein. An experimental instrument: the centrifuge (5810R) is purchased from Eppendorf company, the pipettor is purchased from Eppendorf Domain Rainin company, and the microplate reader is purchased from BioTek company, USA, and the model is SynergyHl full-function microplate reader.

The experimental method comprises the following steps: in vitro SHP-2 Activity assays were performed using the Homogeneous Full Length SHP-2Assay Kit (BPS Bioscience, # 79330). Firstly, 18 μ L of Master Mix was added to a 96-well low adsorption microplate (NUNC, # 267342), i.e. SHP-2activating Peptide and 5mM DTT were contained in a reaction buffer solution with a final concentration of 1 × and then 5 dishes of test compound/DMSO were added per well after centrifugation (final DMSO content 1%, V/V, test compound was dissolved in DMSO to form ImM, three-fold serial dilutions were carried out, 10 concentrations, and the final concentration of the reaction system ranged from 1 μ M to 0.05 nM), SHP-2 was diluted to a final concentration of 0.06nM in a reaction buffer solution with 1 × and then added to a reaction microplate with 2 μ L per well, and a full activity incubation control (compound plus DMSO only) and a full inhibition control (without SHP-2) were set on the reaction plate and the reaction mixture was centrifuged at room temperature for 60 minutes.

After the incubation was complete, 25. Mu.L of Substrate solution per well, containing Substrate at a final concentration of 10. Mu.M and 5mM DTT, was added and incubation continued for 30 minutes at room temperature after centrifugation. After the reaction is finished, the excitation wavelength is set to 340nM, the emission wavelength is set to 455nM, and the gain value is set to 75 on a Synergy Hl full-function microplate reader (Biotek).

The experimental data processing method comprises the following steps:

the percent inhibition ratio data {% inhibition =100- [ (test compound-Min average)/(Max average-Min average) ] X100} for wells treated with compound was calculated from the values of full activity control and full inhibition control as Max and Min by positive control wells (DMSO control wells) and negative control wells (no kinase added) on the reaction plate. IC50 values for test compounds were calculated using GraphPad prism to fit the percent inhibition and ten-point concentration data to a 4-parameter nonlinear logistic formula.

And (4) experimental conclusion:

it was concluded from the above protocol that the compounds of the examples shown in the present invention show biological activities in the SHP-2 kinase activity assay as shown in table 1 below. Wherein "A" represents IC ₅₀ Less than or equal to 10nM; "B" means 10<IC ₅₀ Less than or equal to 100nM; "C" means 100<IC ₅₀ Less than or equal to 1000nM; "D" denotes 1000<IC ₅₀ nM。

IC inhibition of SHP2 by Compounds of Table 1 ₅₀ Value of

Numbering	IC ₅₀	Number of	IC ₅₀	Number of	IC ₅₀
						1	A	13	A	25	A
2	A	14	A	26	A
						3	A	15	A	27	A
4	A	16	A	28	A
						5	A	17	A	29	A
6	A	18	A	30	A
						7	A	19	A	31	A
8	A	20	A	32	A
						9	A	21	A	33	A
10	A	22	A	34	A
						11	A	23	A	35	A
12	A	24	A	36	A

Claims

1. A compound having the general formula (I), a stereoisomer, a pharmaceutically acceptable salt, a polymorph, or an isomer thereof, wherein the compound having the general formula (I) has the following structure:

(I)

wherein,

each L ₂ Independently at each occurrence is selected from the group consisting of bond, O, CH ₂ 、NH、CONH ₂ CO or S;

each X ₁ 、X ₂ 、X ₃ 、X ₅ 、X ₆ 、X ₇ Independently at each occurrence is selected from N, CR ₉ ；

Each R ₉ Independently at each occurrence is selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OC _1-6 、-SC _1-6 、-NHC _1-6 、-N(C _1-6 Alkyl) (C _1-6 Alkyl), CONH ₂ 、COOH；

Each X ₄ Independently at each occurrence is selected from N, C;

each Ar ₁ Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently at each occurrence comprising 1,2, 3 or 4 heteroatoms selected from N, O, or S; each Ar ₁ Independently at each occurrenceOptionally substituted by 1,2, 3, 4, 5 or 6R ₁₉ Substituted or unsubstituted;

each Ar ₂ Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently at each occurrence comprising 1,2, 3 or 4 heteroatoms selected from N, O, or S; each Ar ₂ Optionally at each occurrence independently by 1,2, 3, 4, 5 or 6R ₁₉ Substituted or unsubstituted;

each R ₁₉ Independently at each occurrence, selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OR ₁₀ 、-C _1-6 Alkylene- (OR) ₁₀ ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SR ₁₀ 、-S-C _1-6 Alkylene- (halogen) _1-3 、-NR ₁₀ R ₁₁ -C1-6 alkylene-NR ₁₀ R ₁₁ 、-C(＝O)R ₁₀ 、-C(＝O)OR ₁₀ 、-OC(＝O)R ₁₀ 、-C(＝O)NR ₁₀ R ₁₁ 、-NR ₁₀ C(＝O)R ₁₁ 、-S(O) ₂ NR ₁₀ R ₁₁ or-C _3-6 A carbocyclic group; each R ₁₉ Independently optionally substituted by 1,2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₁₀ 、-NR ₁₀ R ₁₁ 、-CN、-C(＝O)R ₁₀ 、-C(＝O)OR ₁₀ 、-OC(＝O)R ₁₀ 、-C(＝O)NR ₁₀ R ₁₁ 、-NR ₁₀ C(＝O)R ₁₁ or-S (O) ₂ NR ₆ R ₁₁ Substituted or unsubstituted;

each R ₁₀ And R ₁₁ Independently at each occurrence, selected from hydrogen, deuterium or-C _1-6 Alkyl radical, each R ₁₀ And R ₁₁ Independently optionally substituted by 1,2, 3, 4, 5 or 6R ₁₉ Substituted or unsubstituted; or R ₁₀ And R ₁₁ To which they are jointly bound an N atomTaken together to form a 3-10 membered heterocyclic ring, said 3-10 membered heterocyclic ring may further comprise 1,2, 3 or 4 substituents selected from N, O, S (= O) or S (= O) ₂ And said 3-10 membered heterocyclic ring is independently optionally substituted by 1,2, 3, 4, 5 or 6R ₂₀ Substituted or unsubstituted;

each R ₁ Independently at each occurrence, selected from H, deuterium, -C _1-6 An alkyl group;

each R ₄ Independently at each occurrence selected from H, deuterium, OH, C _0-3 NR ₁₂ R ₁₃ ；

Each R ₅ Independently at each occurrence, selected from H, deuterium, OH, C _1-6 Alkyl radical, C _1-6 Alkyl substituted by 1,2, 3, 4, 5 or 6 deuterium, OH, methyl, OCH ₃ 5-10 membered heteroaryl;

each R ₆ Independently at each occurrence, selected from H, deuterium, NH ₂ ；

R ₁ and R ₆ Alkylene groups may be employed to link to form bridged bicyclic rings,

R ₂ and R ₃ Can adopt a quilt NH ₂ Substituted alkylene groups are linked to form a spiro ring,

R ₄ and R ₅ Can be connected to form C _3-12 Cycloalkyl of (C) _3-12 Heterocycloalkyl of (A), C _3-12 Bicycloalkyl of, C _3-12 In which C is _3-12 Heterocycloalkyl of (C) _3-12 Each occurrence of heterobicycloalkyl of (a) independently comprises 1,2, 3 or 4 heteroatoms selected from N, O, or S, each C _3-12 Cycloalkyl of, C _3-12 Heterocycloalkyl of (C) _3-12 Bicycloalkyl of, C _3-12 Independently at each occurrence, optionally deuterium, halogen, OH, CH ₃ 、OCH ₃ 、NH ₂ The substitution forms a spiro ring,

R ₁ and R ₇ Can be connected into bridged double rings through alkylene, O and NH,

R ₂ and R ₇ May be linked through alkylene, O, to form bridged bicyclic rings,

R ₄ and R ₆ Can be prepared through NHCH ₂ Is covered with NH ₂ Substituted C _3-12 The naphthenic base of the benzene ring is connected into a thick double ring,

each a, b, c, d is independently selected at each occurrence from 0, 1;

2. the compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein each

Independently at each occurrence is selected from

And each is

X of (2) ₁ 、X ₂ 、X ₃ 、X ₅ 、X ₆ 、X ₇ Independently at each occurrence is selected from C optionally substituted by 1,2, 3, 4, 5 or 6R ₉ Substituted or unsubstituted;

3. A compound of (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein,

selected from the following structures:

4. a compound of (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein Ar ₁ Independently at each occurrence is selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-A 10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently at each occurrence comprising 1,2, 3, or 4 heteroatoms selected from N, O, or S; each Ar ₁ Optionally at each occurrence independently by 1,2, 3, 4, 5 or 6R ₁₉ Substituted or unsubstituted;

each R ₁₀ And R ₁₁ Independently at each occurrence, selected from hydrogen, deuterium or-C _1-6 Alkyl radical perR is ₁₀ And R ₁₁ Independently optionally substituted by 1,2, 3, 4, 5 or 6R ₁₉ Substituted or unsubstituted; or R ₁₀ And R ₁₁ Together with the N atom to which they are commonly attached form a 3-10 membered heterocyclic ring, which 3-10 membered heterocyclic ring may further comprise 1,2, 3 or 4 substituents selected from N, O, S (= O) or S (= O) ₂ And said 3-10 membered heterocyclic ring is independently optionally substituted with 1,2, 3, 4, 5 or 6R ₂₀ Substituted or unsubstituted;

each R ₂₀ Independently at each occurrence is selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OC _1-6 、-C _1-6 Alkylene- (OC) _1-6 ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SC _1-6 、-S-C _1-6 Alkylene- (halogen) _1-3 or-C _3-6 A carbocyclic group;

5. a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to claims 1 to 4, which is selected from:

or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer, and mixtures and forms thereof.

6. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1-5 or a pharmaceutically acceptable prodrug, stable isotopic derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof.

7. A pharmaceutical formulation comprising a compound of formula (I) as described in any one of claims 1-5 or a pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof or a pharmaceutical composition as described in claim 5, in any one of tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions.

8. A compound of formula (I) as described in any one of claims 1-5 or a pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof, or a pharmaceutical composition as described in claim 6, or a pharmaceutical formulation as described in claim 7 for use in the prevention and treatment of non-receptor protein tyrosine phosphatase mediated or dependent diseases or conditions.

9. Use of a compound of formula (I) as described in any one of claims 1-5 or a pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof, or of a pharmaceutical composition as described in claim 6, or of a pharmaceutical formulation as described in claim 7, for the prevention and/or treatment of a non-receptor protein tyrosine phosphatase mediated or dependent disease or condition.

10. Use of a compound of formula (I) as claimed in any one of claims 1 to 5 or a pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer and mixtures and forms thereof, or a pharmaceutical formulation as claimed in claim 5 in the manufacture of a medicament for the prophylaxis and/or treatment of a non-receptor protein tyrosine phosphatase mediated or dependent disease or condition.

11. Use of a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the prevention or treatment of noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute bone leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, pancreatic cancer, head and neck squamous cell carcinoma, gastric cancer, liver cancer, anaplastic large-cell lymphoma and glioblastoma.